REGULATION OF INTERLEUKIN-6 PRODUCTION IN HUMAN FETAL KUPFFER CELLS

Inflammatory mediators such as interleukin-1 beta (IL-1-beta), tumour necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) exhibit local autocrine and paracrine effects as well as distant systemic effects on target cells. Human Kupffer cells, the fixed tissue macrophages of the liver, may modulate immune and endocrine function in early fetal development. We purified and cultured human fetal Kupffer cells to investigate the production of the cytokine, IL-6. Fetal Kupffer cells treated with bacterial lipopolysaccharide (LPS) produced IL-6 in a dose-dependent fashion with maximal secretion (1000 pg per 10(6) cells) observed within 12 h using 10-mu-g of LPS/ml. Cortisol and dexamethasone, but not oestrogen, progesterone, or testosterone, dramatically suppressed the LPS-stimulated secretion of IL-6 by fetal Kupffer cells. None of the steroids tested altered basal production or enhanced the LPS-stimulated production of IL-6 by fetal Kupffer cells. The inhibition of glucococorticoids could be reversed by the addition of RU 486, indicating that this effect was mediated by the glucocorticoid receptor. These results demonstrate that the production of IL-6 by fetal hepatic macrophages can be activated by LPS and suppressed by glucocorticoids. These studies suggest that Kupffer cells express mature macrophage function in early gestation and would be capable of regulatory roles in the growth and development of the fetus.